Abstract

The canonical vertebrate neurotrophin receptors — the Trk and p75\(^N\)\(^T\)\(^R\) protein families — have not been found in Drosophila, thus it is unclear how neurotrophic signalling is implemented in fruit flies. The Drosophila genome encodes 9 proteins with extracellular domain compositions resembling vertebrate Trks, but lacking an intracellular tyrosine kinase. Here, I investigated whether these 9 proteins, plus 3 further candidates, can function as receptors of the Drosophila neurotrophins (DNTs). Initial characterisation of the candidate proteins highlighted the Kekkon (Kek) family as potential receptors. After tool and mutant generation, I showed that: (1) kek2, kek3 and kek6 overexpression rescues the semi-lethality of DNT1DNT2 double mutants; (2) Kek3, Kek4 and Kek6 interact with DNT2 ligand, eliciting a luciferase readout in S2 cells; and (3) kek3, kek4 and kek6 genetically interact with DNT1 and DNT2. Further analysis revealed Kek6 is expressed in, and required for targeting of, motor neurons, and has a role in locomotion. Surprisingly, Kek4 was enriched in the larval ring gland and affected developmental timing by inhibiting juvenile hormone. Together, data revealed the Keks function in neurodevelopment and growth regulation, and interact with the DNTs. The work uncovered functional conservation of protein domains in neurodevelopment despite domain shuffling throughout the animal kingdom.